Myelin protein zero mutation‐related hereditary neuropathies: Neuropathological insight from a new nerve biopsy cohort

Abstract

Myelin protein zero (MPZ/P0) is a major structural protein of peripheral nerve myelin. Disease‐associated variants in the MPZ gene cause a wide phenotypic spectrum of inherited peripheral neuropathies. Previous nerve biopsy studies showed evidence for subtype‐specific morphological features. Here, we aimed at enhancing the understanding of these subtype‐specific features and pathophysiological aspects of MPZ neuropathies. We examined archival material from two Central European centers and systematically determined genetic, clinical, and neuropathological features of 21 patients with MPZ mutations compared to 16 controls. Cases were grouped based on nerve conduction data into congenital hypomyelinating neuropathy (CHN; n = 2), demyelinating Charcot–Marie‐Tooth (CMT type 1; n = 11), intermediate (CMTi; n = 3), and axonal CMT (type 2; n = 5). Six cases had combined muscle and nerve biopsies and one underwent autopsy. We detected four MPZ gene variants not previously described in patients with neuropathy. Light and electron microscopy of nerve biopsies confirmed fewer myelinated fibers, more onion bulbs and reduced regeneration in demyelinating CMT1 compared to CMT2/CMTi. In addition, we observed significantly more denervated Schwann cells, more collagen pockets, fewer unmyelinated axons per Schwann cell unit and a higher density of Schwann cell nuclei in CMT1 compared to CMT2/CMTi. CHN was characterized by basal lamina onion bulb formation, a further increase in Schwann cell density and hypomyelination. Most late onset axonal neuropathy patients showed microangiopathy. In the autopsy case, we observed prominent neuromatous hyperinnervation of the spinal meninges. In four of the six muscle biopsies, we found marked structural mitochondrial abnormalities. These results show that MPZ alterations not only affect myelinated nerve fibers, leading to either primarily demyelinating or axonal changes, but also affect non‐myelinated nerve fibers. The autopsy case offers insight into spinal nerve root pathology in MPZ neuropathy. Finally, our data suggest a peculiar association of MPZ mutations with mitochondrial alterations in muscle.

Charcot–Marie–Tooth Disease with Myelin Protein Zero Mutation Presenting as Painful, Predominant Small-Fiber Neuropathy

“…In other patients, sural-nerve biopsy showed clusters of regenerating fibers, possibly acting as irritable nociceptors [17,22]. These findings, however, are not specific for MPZ mutations, nor obligatorily associated with pain symptoms [37].…”

The Influence of Lysosomal Stress on Dental Pulp Stem Cell-Derived Schwann Cells

“…Both markers increased for all donor lines following the differentiation, and we observed a significant increase in S100B for donor 2, whereas p75 NTR significantly increased in all donor lines. The gene expression levels of MPZ, the most abundant protein of the PNS myelin sheath [27], significantly increased in donor line 1, and increased (non-significantly) for donor lines 2 and 3. LAMA2, a key component of the Schwann cell basal lamina and crucial for Schwann cell differentiation [28,29], significantly increased in all lines.…”